Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques.

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires

People Are Unable to Recognize or Report on Their Own Eye Movements

Eye movements bring new information into our visual system. The selection of each fixation is the result of a complex interplay of image features, task goals, and biases in motor control and perception. To what extent are we aware of the selection of saccades and their consequences? Here we use a converging methods approach to answer this question in three diverse experiments. In Experiment 1, participants were directed to find a target in a scene by a verbal description of it. We then presented the path the eyes took together with those of another participant. Participants could only identify their own path when the comparison scanpath was searching for a different target. In Experiment 2, participants viewed a scene for three seconds and then named objects from the scene. When asked whether they had looked directly at a given object, participants’ responses were primarily determined by whether or not the object had been named, and not by whether it had been fixated. In Experiment 3, participants executed saccades towards single targets and then viewed a replay of either the eye movement they had just executed or that of someone else. Participants were at chance to identify their own saccade, even when it contained under- and overshoot corrections. The consistent inability to report on one's own eye movements across experiments suggests that awareness of eye movements is extremely impoverished or altogether absent. This is surprising given that information about prior eye movements is clearly used during visual search, motor error correction, and learning

Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England

Objectives The National Health Service in England funds 12 months of weekly s.c. tocilizumab (qwTCZ) for patients with relapsing or refractory GCA. During the coronavirus disease 2019 (COVID-19) pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. Methods Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. Results A total of 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median [interquartile range (IQR)] of 12 (12–17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0–5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6%, respectively, had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10–40) mg/day. 33.6% relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017), in those not in remission at qwTCZ cessation (P = 0.0036) and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65 years, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing and conventional synthetic DMARD use were not associated with time to relapse. Conclusion Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One-third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients

HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

Summary Broadly neutralizing antibodies (bnAbs) against the N332 supersite of the HIV envelope (Env) trimer are the most common bnAbs induced during infection, making them promising leads for vaccine design. Wild-type Env glycoproteins lack detectable affinity for supersite-bnAb germline precursors and are therefore unsuitable immunogens to prime supersite-bnAb responses. We employed mammalian cell surface display to design stabilized Env trimers with affinity for germline-reverted precursors of PGT121-class supersite bnAbs. The trimers maintained native-like antigenicity and structure, activated PGT121 inferred-germline B cells ex vivo when multimerized on liposomes, and primed PGT121-like responses in PGT121 inferred-germline knockin mice. Design intermediates have levels of epitope modification between wild-type and germline-targeting trimers; their mutation gradient suggests sequential immunization to induce bnAbs, in which the germline-targeting prime is followed by progressively less-mutated design intermediates and, lastly, with native trimers. The vaccine design strategies described could be utilized to target other epitopes on HIV or other pathogens

Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England

OBJECTIVES: The National Health Service in England funds 12 months of weekly subcutaneous tocilizumab (qwTCZ) for patients with relapsing or refractory giant cell arteritis (GCA). During the COVID-19 pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. METHODS: Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. RESULTS: 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median (interquartile range, IQR) of 12 (12-17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0-5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6% respectively had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10-40) mg/day. 33.6% of relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017); in those not in remission at qwTCZ cessation (P = 0.0036); and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing, and conventional synthetic DMARD use were not associated with time to relapse. CONCLUSION: Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text

Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques.

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires